Tau binding protein CAPON induces tau aggregation and neurodegeneration

Shoko Hashimoto (), Yukio Matsuba, Naoko Kamano, Naomi Mihira, Naruhiko Sahara, Jiro Takano, Shin-ichi Muramatsu, Takaomi C. Saido () and Takashi Saito ()
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Shoko Hashimoto: RIKEN Center for Brain Science
Yukio Matsuba: RIKEN Center for Brain Science
Naoko Kamano: RIKEN Center for Brain Science
Naomi Mihira: RIKEN Center for Brain Science
Naruhiko Sahara: National Institutes for Quantum and Radiological Science and Technology
Jiro Takano: RIKEN Center for Brain Science
Shin-ichi Muramatsu: Jichi Medical University
Takaomi C. Saido: RIKEN Center for Brain Science
Takashi Saito: RIKEN Center for Brain Science

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract To understand the molecular processes that link Aβ amyloidosis, tauopathy and neurodegeneration, we screened for tau-interacting proteins by immunoprecipitation/LC-MS. We identified the carboxy-terminal PDZ ligand of nNOS (CAPON) as a novel tau-binding protein. CAPON is an adaptor protein of neuronal nitric oxide synthase (nNOS), and activated by the N-methyl-D-aspartate receptor. We observed accumulation of CAPON in the hippocampal pyramidal cell layer in the AppNL-G-F -knock-in (KI) brain. To investigate the effect of CAPON accumulation on Alzheimer’s disease (AD) pathogenesis, CAPON was overexpressed in the brain of AppNL-G-F mice crossbred with MAPT (human tau)-KI mice. This produced significant hippocampal atrophy and caspase3-dependent neuronal cell death in the CAPON-expressing hippocampus, suggesting that CAPON accumulation increases neurodegeneration. CAPON expression also induced significantly higher levels of phosphorylated, oligomerized and insoluble tau. In contrast, CAPON deficiency ameliorated the AD-related pathological phenotypes in tauopathy model. These findings suggest that CAPON could be a druggable AD target.

Date: 2019
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DOI: 10.1038/s41467-019-10278-x

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